The long term goal of this project is to uncover the fundamental physical processes underlying nervous excitation and conduction i.e. the molecular mechanisms by which nerve and other excitable cells generate the action potential and other electrical signals. To this end studies will be conducted on the gating (process by which channels change their availability for ion passage as a response to changes in the applied field) of and ion permeation (physical process by which ions traverse cell membranes) through ionic channels in the membranes of internally perfused, voltage clamped giant axons and through single channels in skeletal muscle. Channel gating studies are aimed at developing a compelling picture of the organization of the Na channel gating machinery utilizing combined chemical kinetic analysis of both the ionic and asymmetrical displacement currents. In this same vein pharmacological treatments producing identical kinetic effects in Na channel activation and in the early part of the time course of inactivation can be used to provide definitive evidence for the idea that some fraction of channels must conduct before they can inactivate. For permeation, studies on the nature of the changes in Na channel selectivity produced by internal alkali cations argue for the idea of ion-ion interactions within the Na channel.